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Nature Reviews. Drug Discovery Dec 2019Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in... (Review)
Review
Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases - including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease - this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.
Topics: Animals; Energy Metabolism; Enzyme Replacement Therapy; Humans; Lysosomal Storage Diseases; Lysosomes; Neurodegenerative Diseases; Proteins
PubMed: 31477883
DOI: 10.1038/s41573-019-0036-1 -
Revista Chilena de Pediatria 2016The mucopolysaccharidoses (MPS) are a group of rare (orphan) diseases, characterised by a deficiency of enzymes involved in the metabolism of glycosaminoglycans (GAGs)... (Review)
Review
The mucopolysaccharidoses (MPS) are a group of rare (orphan) diseases, characterised by a deficiency of enzymes involved in the metabolism of glycosaminoglycans (GAGs) at lysosomal level. When there is a deficiency of a particular enzyme there is an accumulation of GAGs in the cells resulting in progressive cellular damage, which can affect multiple organ systems and lead to organ failure. Diagnosis is based on knowledge of the clinical manifestations, performing biochemical analyses to identify the type of GAG that is accumulating, and confirm the type of disorder with the corresponding enzymatic determination. Their identification is essential to initiate early treatment, taking into account that multidisciplinary management and enzyme replacement therapy is available for MPS I (Hurler syndrome), MPS II (Hunter syndrome), MPS IV (Morquio syndrome), and MPS VI (Maroteaux-Lamy syndrome. In this review, an analysis is made of each of these syndromes, as well as their diagnosis and treatment.
Topics: Animals; Enzyme Replacement Therapy; Glycosaminoglycans; Humans; Mucopolysaccharidoses
PubMed: 26613630
DOI: 10.1016/j.rchipe.2015.10.004 -
Gut Aug 2017The benefits of pancreatic enzyme replacement therapy (PERT) in chronic pancreatitis (CP) are inadequately defined. We have undertaken a systematic review and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The benefits of pancreatic enzyme replacement therapy (PERT) in chronic pancreatitis (CP) are inadequately defined. We have undertaken a systematic review and meta-analysis of randomised controlled trials of PERT to determine the efficacy of PERT in exocrine pancreatic insufficiency (EPI) from CP.
DESIGN
Major databases were searched from 1966 to 2015 inclusive. The primary outcome was coefficient of fat absorption (CFA). Effects of PERT versus baseline and versus placebo, and of different doses, formulations and schedules were determined.
RESULTS
A total of 17 studies (511 patients with CP) were included and assessed qualitatively (Jadad score). Quantitative data were synthesised from 14 studies. PERT improved CFA compared with baseline (83.7±6.0 vs 63.1±15.0, p<0.00001; I=89%) and placebo (83.2±5.5 vs 67.4±7.0, p=0.0001; I=86%). PERT improved coefficient of nitrogen absorption, reduced faecal fat excretion, faecal nitrogen excretion, faecal weight and abdominal pain, without significant adverse events. Follow-up studies demonstrated that PERT increased serum nutritional parameters, improved GI symptoms and quality of life without significant adverse events. High-dose or enteric-coated enzymes showed a trend to greater effectiveness than low-dose or non-coated comparisons, respectively. Subgroup, sensitive and meta-regression analyses revealed that sample size, CP diagnostic criteria, study design and enzyme dose contributed to heterogeneity; data on health inequalities were lacking.
CONCLUSIONS
PERT is indicated to correct EPI and malnutrition in CP and may be improved by higher doses, enteric coating, administration during food and acid suppression. Further studies are required to determine optimal regimens, the impact of health inequalities and long-term effects on nutrition.
Topics: Dietary Fats; Enzyme Therapy; Enzymes; Exocrine Pancreatic Insufficiency; Feces; Humans; Nutritional Status; Pancreas; Pancreatitis, Chronic; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 27941156
DOI: 10.1136/gutjnl-2016-312529 -
Medicina (Kaunas, Lithuania) Oct 2020Exocrine pancreatic insufficiency (EPI) is defined as the maldigestion of foods due to inadequate pancreatic secretion, which can be caused by alterations in its... (Review)
Review
Exocrine pancreatic insufficiency (EPI) is defined as the maldigestion of foods due to inadequate pancreatic secretion, which can be caused by alterations in its stimulation, production, transport, or interaction with nutrients at duodenal level. The most frequent causes are chronic pancreatitis in adults and cystic fibrosis in children. The prevalence of EPI is high, varying according to its etiology, but it is considered to be underdiagnosed and undertreated. Its importance lies in the quality of life impairment that results from the malabsorption and malnutrition and in the increased morbidity and mortality, being associated with osteoporosis and cardiovascular events. The diagnosis is based on a set of symptoms, indicators of malnutrition, and an indirect non-invasive test in at-risk patients. The treatment of choice combines non-restrictive dietary measures with pancreatic enzyme replacement therapy to correct the associated symptoms and improve the nutritional status of patients. Non-responders require the adjustment of pancreatic enzyme therapy, the association of proton pump inhibitors, and/or the evaluation of alternative diagnoses such as bacterial overgrowth. This review offers an in-depth overview of EPI in order to support the proper management of this entity based on updated and integrated knowledge of its etiopathogenesis, prevalence, diagnosis, and treatment.
Topics: Child; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Humans; Pancreas; Pancreatitis, Chronic; Quality of Life
PubMed: 33036352
DOI: 10.3390/medicina56100523 -
World Journal of Gastroenterology Nov 2013Pancreatic exocrine insufficiency is an important cause of maldigestion and a major complication in chronic pancreatitis. Normal digestion requires adequate stimulation... (Review)
Review
Pancreatic exocrine insufficiency is an important cause of maldigestion and a major complication in chronic pancreatitis. Normal digestion requires adequate stimulation of pancreatic secretion, sufficient production of digestive enzymes by pancreatic acinar cells, a pancreatic duct system without significant outflow obstruction and adequate mixing of the pancreatic juice with ingested food. Failure in any of these steps may result in pancreatic exocrine insufficiency, which leads to steatorrhea, weight loss and malnutrition-related complications, such as osteoporosis. Methods evaluating digestion, such as fecal fat quantification and the (13)C-mixed triglycerides test, are the most accurate tests for pancreatic exocrine insufficiency, but the probability of the diagnosis can also be estimated based on symptoms, signs of malnutrition in blood tests, fecal elastase 1 levels and signs of morphologically severe chronic pancreatitis on imaging. Treatment for pancreatic exocrine insufficiency includes support to stop smoking and alcohol consumption, dietary consultation, enzyme replacement therapy and a structured follow-up of nutritional status and the effect of treatment. Pancreatic enzyme replacement therapy is administered in the form of enteric-coated minimicrospheres during meals. The dose should be in proportion to the fat content of the meal, usually 40-50000 lipase units per main meal, and half the dose is required for a snack. In cases that do not respond to initial treatment, the doses can be doubled, and proton inhibitors can be added to the treatment. This review focuses on current concepts of the diagnosis and treatment of pancreatic exocrine insufficiency.
Topics: Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Humans; Pancreatic Function Tests; Pancrelipase; Predictive Value of Tests; Proton Pump Inhibitors; Risk Factors; Risk Reduction Behavior; Treatment Outcome
PubMed: 24259956
DOI: 10.3748/wjg.v19.i42.7258 -
Current Neuropharmacology 2023Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality. (Review)
Review
BACKGROUND
Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality.
OBJECTIVE
The aim of this narrative review is to present the current and novel therapeutic strategies in FD, including symptomatic and specific treatment options.
METHODS
A systematic literature search was conducted to identify relevant studies, including completed and ongoing randomized-controlled clinical trials (RCTs), prospective or retrospective cohort studies, case series and case reports that provided clinical data regarding FD treatment.
RESULTS
A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity. During the last two decades, FD-specific treatments, including two enzyme-replacement-therapies (agalsidase alfa and agalsidase beta) and chaperone treatment with migalastat have been approved for use and allowed for symptoms' stabilization or even disease burden reduction. More therapeutic agents are currently under investigation. Substrate reduction therapies, including lucerastat and venglustat, have shown promising results in RCTs and may be used either as monotherapy or as complementary therapy to established enzymereplacement- therapies. More stable enzyme-replacement-therapy molecules that are associated with less adverse events and lower likelihood of neutralizing antibodies formation have also been developed. Ex-vivo and in-vivo gene therapy is being tested in animal models and pilot human clinical trials, with preliminary results showing a favorable safety and efficacy profile.
CONCLUSION
The therapeutic landscape in FD appears to be actively expanding with more treatment options expected to become available in the near future, allowing for a more personalized approach in FD patients.
Topics: Animals; Humans; Fabry Disease; 1-Deoxynojirimycin; Enzyme Replacement Therapy
PubMed: 35652398
DOI: 10.2174/1570159X20666220601124117 -
Orphanet Journal of Rare Diseases Jun 2022Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the effects of treatment on... (Review)
Review
BACKGROUND
Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the effects of treatment on large patient populations with rare diseases. The year 2021 marks the 20th anniversary of the Fabry Outcome Survey (FOS), an international, multicenter, observational registry (NCT03289065). The primary aims of FOS are to broaden the understanding of Fabry disease (FD), an X-linked lysosomal storage disorder, and to improve the clinical management of affected patients. Here, we review the history of FOS and the analyses and publications disseminated from the registry, and we discuss the contributions FOS studies have made in understanding FD.
RESULTS
FOS was initiated in April 2001 and, as of January 2021, 4484 patients with a confirmed diagnosis and patient informed consent have been enrolled from 144 centers across 26 countries. Data from FOS have been published in nearly 60 manuscripts on a wide variety of topics relevant to FD. Analyses of FOS data have investigated the long-term effectiveness and safety of enzyme replacement therapy (ERT) with agalsidase alfa and its effects on morbidity and mortality, as well as the benefits of prompt and early treatment with agalsidase alfa on the progression of cardiomyopathy and the decline in renal function associated with FD. Based on analyses of FOS data, ERT with agalsidase alfa has also been shown to improve additional signs and symptoms of FD experienced by patients. FOS data analyses have provided a better understanding of the natural history of FD and the specific populations of women, children, and the elderly, and have provided practical tools for the study of FD. FOS has also provided methodology and criteria for assessing disease severity which contributed to the continuous development of medical practice in FD and has largely improved our understanding of the challenges and needs of long-term data collection in rare diseases, aiding in future rare disease real-world evidence studies.
CONCLUSION
FOS over the last 20 years has substantially increased the scientific knowledge around improved patient management of FD and continues to expand our understanding of this rare disease.
Topics: Aged; Child; Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Multicenter Studies as Topic; Rare Diseases; Recombinant Proteins; Registries; Treatment Outcome; alpha-Galactosidase
PubMed: 35725623
DOI: 10.1186/s13023-022-02392-9 -
International Journal of Molecular... May 2018Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the... (Review)
Review
Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the lysosomal α-d-mannosidase. So far, 155 variants from 191 patients have been identified and in part characterized at the biochemical level. Similarly to other lysosomal storage diseases, there is no relationship between genotype and phenotype in alpha-mannosidosis. Enzyme replacement therapy is at the moment the most effective therapy for lysosomal storage disease, including alpha-mannosidosis. In this review, the genetic of alpha-mannosidosis has been described together with the results so far obtained by two different therapeutic strategies: bone marrow transplantation and enzyme replacement therapy. The primary indication to offer hematopoietic stem cell transplantation in patients affected by alpha-mannosidosis is preservation of neurocognitive function and prevention of early death. The results obtained from a Phase I⁻II study and a Phase III study provide evidence of the positive clinical effect of the recombinant enzyme on patients with alpha-mannosidosis.
Topics: Animals; Bone Marrow Transplantation; Combined Modality Therapy; Enzyme Activation; Enzyme Replacement Therapy; Genetic Association Studies; Humans; Mutation; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 29772816
DOI: 10.3390/ijms19051500 -
Drugs Jun 2023Cipaglucosidase alfa (Pombiliti) is a recombinant human acid α-glucosidase (GAA) product being developed by Amicus Therapeutics along with the enzyme stabilizer... (Review)
Review
Cipaglucosidase alfa (Pombiliti) is a recombinant human acid α-glucosidase (GAA) product being developed by Amicus Therapeutics along with the enzyme stabilizer miglustat as a two-component therapy for Pompe disease. Pompe disease is a rare, inherited lysosomal disease caused by a deficiency of the enzyme GAA, which leads to accumulation of glycogen in various tissues. On 27 March 2023, cipaglucosidase alfa was approved in the EU as a long-term enzyme replacement therapy (ERT) used in combination with miglustat for the treatment of adults with late-onset Pompe disease. This article summarizes the milestones in the development of cipaglucosidase alfa leading to this first approval.
Topics: Adult; Humans; Glycogen Storage Disease Type II; 1-Deoxynojirimycin; Enzyme Replacement Therapy; Glycogen
PubMed: 37184753
DOI: 10.1007/s40265-023-01886-5 -
Molecules (Basel, Switzerland) Feb 2021Many cancer diseases, e.g., prostate cancer and lung cancer, develop very slowly. Common chemotherapeutics like vincristine, vinblastine and taxol target cancer cells in... (Review)
Review
Many cancer diseases, e.g., prostate cancer and lung cancer, develop very slowly. Common chemotherapeutics like vincristine, vinblastine and taxol target cancer cells in their proliferating states. In slowly developing cancer diseases only a minor part of the malignant cells will be in a proliferative state, and consequently these drugs will exert a concomitant damage on rapidly proliferating benign tissue as well. A number of toxins possess an ability to kill cells in all states independently of whether they are benign or malignant. Such toxins can only be used as chemotherapeutics if they can be targeted selectively against the tumors. Examples of such toxins are mertansine, calicheamicins and thapsigargins, which all kill cells at low micromolar or nanomolar concentrations. Advanced prodrug concepts enabling targeting of these toxins to cancer tissue comprise antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), lectin-directed enzyme-activated prodrug therapy (LEAPT), and antibody-drug conjugated therapy (ADC), which will be discussed in the present review. The review also includes recent examples of protease-targeting chimera (PROTAC) for knockdown of receptors essential for development of tumors. In addition, targeting of toxins relying on tumor-overexpressed enzymes with unique substrate specificity will be mentioned.
Topics: Antineoplastic Agents; Apoptosis; Calicheamicins; Cell Proliferation; Delayed-Action Preparations; Drug Carriers; Drug Design; Drug Liberation; Enzyme Therapy; Gene Knockdown Techniques; Humans; Lung Neoplasms; Male; Maytansine; Molecular Targeted Therapy; Peptide Hydrolases; Prodrugs; Prostatic Neoplasms; Thapsigargin; Toxins, Biological
PubMed: 33673582
DOI: 10.3390/molecules26051292